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In part 2 of the lecture Differentiating Infected from Non-Infected Wounds, Im going to concentrate on the treatment of these wounds. In particular Im going to concentrate on topical antimicrobial therapy and what is the evidence behind the use of topical antimicrobials to decolonize these wounds or actually treat clinical infection. In particular, Ill discuss topical antibiotic therapy, various dressings with a concentration on the use of silver dressings and then some of the newer solutions in particular the chlorine-based solutions that are being used as topical therapy for these wounds.
Production of this present lecture was made possible by a generous grant from PuriCore, developers of the exciting and new wound care technology; vashe wound therapy, the powerful nature of wound therapy.
This is just a graphic demonstrating some of the points I was making, courtesy of my colleague Dr. Ben Lipsky. What it is shows is again, doing a superficial swab thats just bad and its not good to practice, you would get a lot of contamination, a lot of junk that doesnt necessarily mean anything. Whereas curettage of the ulcer based can also be a reasonable technique, just like I talk about the qualitative swab or semi-quantitative swab applying some pressure, the concept is you need to get deeper tissue; I dont care whether you do that the curettage or applying pressure to the swab as you are taking the culture. As long as you are getting tissue and fluid from deeper in the wound thats okay. If you really want deep tissue or deep wound fluid, what about the aspiration? I cant recommend that, frankly if you stick a needle in to an infected area to me, all youre doing is running the risk of inoculating bacteria more deeply. And there were some studies that were published in the late 70s or early 80s, it actually showed the recovery of bacteria from aspirates of leading edge cellulites for example really do not show much and have less than 10% of recovery.
Going back to the whole issue of the so-called gold standard of quantitative biopsies for diagnosing infection in wounds. I want to explore that a little bit more detail, there really is little to know evidence of this long health belief that 10 to the 5th and 10 to the 6th organisms is somehow some magic number that defines infection. So if you really dont even know that the means anything, why put the patient through it. The information that you obtained is really of questionable importance. You can certainly have wounds with 10 to the 5th organisms, 10 to the 6th organisms are more that are not clinically infected; maybe theyre just critically colonized at that point. And also some of these wounds are going to be polymicrobial, youre going to find lots of different organisms. Whats the importance of that? What implications does that give? We talked earlier about how sometimes whats more important is which organisms are present as opposed to how many organisms are present. Furthermore, the technique of doing biopsies for cultures is time-consuming, its costly and you need to have a lab that knows what theyre doing, that knows how to take the tissue specimen and properly plate it out and count the colonies and you need have practitioners who have the ability to take this specific biopsy thats necessary. So theres all this downside to this whole idea of doing quantitative cultures or biopsies for cultures with very, very little upside in my opinion.
Up until this point of the lecture, Ive explored questions such as whether wound is infected or not infected, how to determine that, the wound infection continuum colonization, critical colonization, how to take cultures. Well lets switch gears a little bit now and actually explore the whole question of antimicrobial uses in wounds and when should we use antimicrobial and when should we maybe not use antimicrobials. Well I think a basic statement that we can start this section off is just the routine use of systemic antibiotics in clinically uninfected wounds is not supported by the evidence. You dont want to overuse antibiotics. Why? Overuse of antibiotics lead to resistant organisms, this is one of the reasons we are where we are with the MRSA problems we have now and the whole multidrug resistant gram negatives with extended spectrum beta lactamase productions thats happening. So, right off the top level, do not use systemic antibiotics in clinically non-infected wounds, its just not supported by any sort of medical evidence.
Well if Im telling you not to use systemic antibiotics and we know these bacteria are there on the wound, what about topical antimicrobials, what role do they play. And I really think that what ever you looking at a topical antimicrobial, be it a dressing, be it an antibiotic, be it an antiseptic wound solution, I think there are three basic questions that need to be answered, and at least to my satisfaction, really have not been answered with any the products that are currently available. And the first question is - can we assume the topical antimicrobial decreases the bioburden and it sounds pretty straight forward. I mean of course if you going to put something thats antimicrobial on some bacteria, it should decrease the bioburden. But Im going to show you with one of the studies at least on one of the products that maybe thats not really the case, so, most products yes probably we know that we can decrease bioburden, but then we have to question is there really an importance to that? Which brings up question number two, by reducing that bioburden will we heal the wound more quickly? And I dont think that question has been really addressed properly either because frankly it would a little tough to develop these randomized controlled trials. But will reduction in that bioburden heal a wound more quickly, another question that needs to be ask, and finally the third question that needs to be asked - by reducing that bioburden, can we prevent a non-infected wound from becoming infected. Larry Lavery showed in a landmark study a number of years ago that 50% of all diabetic foot ulcerations at sometime during the life cycle of that ulcer are going to become clinically infected and require systemic antibiotics. Well if we, by reducing the topical bioburden, can change that number to maybe 30% or 20%, think of what we can say in terms of limbs and cost for treating these wounds. These are the three questions I think that we have to ask when somebody comes to us to talk about topical antimicrobials and quite frankly I think that companies that are producing these antimicrobials ne it again - dressing, solutions, antibiotics, whatever, also have to a ask themselves and be held to that standard.
So lets look at some of topical antimicrobials that are currently available and we can break these products down into three categories. The first being actually antibiotic drugs. This include a particular topical drug quote Pexiganan and the low class of whatever known as peptides antibiotics, theres a drug that been around for a long time but not in the United States called fusidic acid and relatively new antibiotic called Retapamulin which is indicated in the United States for some uses and we will go into those in a little bit more detail. Next are dressing an of course if we looking at antimicrobial dressings we primarily looking at the silver-containing dressings and theres been interesting works that looks at the efficacy of silver containing dressings, and then there also a miscellaneous topical solutions in gels, oak barks extract containing products, theres a super oxidized water out there in the market and theres also hypochlorous acid solution thats also currently available. Well look into each of these in some detail.
The first of antibiotics to discuss is the drug called Pexiganan, now Pexiganan is a peptide class antibiotic and really this is relatively a newly discovered class of antibiotics that are actually produced by living organisms usually as a protective device or protective coating against their environment. And in fact Pexiganan was derived from the skin of the Amazon clawed swamp frog, theres actually quite a story behind this. It was invented by a M.D. Ph.D. by the name of Michael Zasloff who is doing some work for the NIH on this Amazon clawed swap frog. He was doing oophorectomy, taking up their ovaries and he would cruelly suture the incisions back together after he did oophorectomy and put the frog back into their slimy disgusting swampy water and he came to this realization that these frogs were not getting infected so there must something in the skin of the frog that was producing an antibiotic and preventing them from becoming infected and after much work, they discovered that the frog was capable of producing this peptide antibiotic which was then synthesized and became known as this product Pexiganan. Now pivotal trial was performed on this almost ten years ago even though it was recently published by Ben Lipsky in Clinical Infectious Diseases back in the 2008. And what the trial did is looked at 835 patients with mild diabetic foot infections and it compared topical pexiganan versus oral ofloxacin and there was actually equivalence found in clinical improvement, microbiological eradication and wound healing. And on top of that it was found that resistance emerged on ofloxacin but not on the pexiganan. Unfortunately there was some problems in the manufacture of this drug, the drug changed hands a number of times, the FDA initially did not accept the product and it become an orphan sort of drug and unfortunately just recently within the last couple of weeks of this recording, I heard that the company that originally developed it called Magainin Pharmaceuticals Inc. changed names and became Gaenera Pharmaceuticals actually ceased to exist. So this products is out there somewhere, there is some very interesting science behind it, so it may be an effective topical for the treatment of mildly infected diabetic foot ulcerations, we just dont have it yet and unfortunately I dont know whether we will or will not even get it. But I do think its worth including for completeness sake in this lecture.
Fusidic acid is another antibiotic that has been used topically for many, many years and its a unique fusidane class antibiotics. You probably not familiar with that because frankly there are no other fusidane antibiotics that are available and none of them are available in United States. Its actually similar structure to steroids but has no steroid activity. Whats interesting about this is when its used topically, it actually penetrates very well in the tissues including in the abscess and thats been shown that it was very effective without even necessarily performing drainage on the abscess. Its available both topically and orally but heres the kicker, its not available in the United States and although some companies have talked to the manufacturer about bringing this in to the country, it just never has been through the FDA and its not been released but for anybody who maybe listening to this lecture whose ex USA, you know, Canada, Mexico and in Europe, this is a very good broad spectrum drug particularly effective against gram positives that may be used as a topical therapy for a skin structure infections. It is active against MRSA and is most frequently used in burns and impetigo. But as with just about any drug thats used and any antibiotics, theres a potential for resistance especially when drugs have gotten increased usage because of MRSA even drugs such as mupirocin which is being used a lot for de-colonization, your [___] to with overuse get resistance. So, an interesting drug again not available in the US but worth including for those of you outside the United Stated and for completeness sake.
Retapamulin is an antibiotic that is actually available in the US; it is FDA-approved, unfortunately not for wounds at this point. It is a very good anti-staphylococal agent including having activity gets methicillin resistant staphylococcus aureus. Unfortunately in United States, although it is approved and marketed under the name of Altabax, it is only approved to this point for impetigo and we dont see a lot of impetigo on the foot so its not something that were going to be using a lot of. However, in other parts of the world it is used for things other than impetigo and that includes in the European Union being approved for lacerations, abrasions and even sutured wounds. So it is interesting to see that come to the United States and those indications that we studied here in the United States, Im just not aware whether or not the company is thinking of doing that. It was found not inferior to cephalexin for infected traumatic wound and infected dermatitis. Unfortunately again, theres no diabetic foot data, so this is a very interesting promising drug Id like to see its studied here in United States and maybe eventually obtain approval for some of its other topical uses and maybe the world will eventually get out to the company that produces this that this might be good market to explore.
I think its really important to discuss silver dressings because you cant pick up a journal be it a podiatric journal, a surgical journal, or a wound healing journal without seeing ads for new silver compounds, new silver dressings. You cant go to a meeting nowadays without the exhibit hall literally being plastered with silver dressings. Theres some many of them that are out there, I think its really important to explore what evidence it is behind this and really what they do and what they dont do. Well, we do know that the silver ion is a potent broad spectrum antimicrobial and again lets get back to those three questions I asked a little bit earlier - can these dressings de-colonize a wound? By de-colonizing the wound, do we get faster healing? And by de-colonizing the wound, do we prevent infection? So these silver dressings are broad spectrum topical antimicrobials. Lets see if any of those questions are answered. Originally, dressings had silver included not to treat the wound; the idea putting silver in the dressing was not to de-colonize the wound. Rather the reason for putting silver in the dressing is because the organisms in the fluid that got sucked up into the dressing would then be killed so that would reduce the bacterial load in the dressing not necessarily in the wound which will lead to the need for less frequent dressing changes. So it was really a convenience issue more than a wound treatment issue, by killing the bacteria that were in the drainage, maybe the wound dressings could be changed less frequently. Now as I mentioned, there are just countless varieties of dressings containing silver just about every form, alginates, gels, foams, you name it, you can find them with silver. The problem is all of these silver dressings have what are called a 510K approval through the FDA. In other words theyre approved as medical devices, not drugs so unlike the pharmaceutical companies that have to go through all of these randomized controlled registration trials in order to get an approval as a pharmaceutical agent, a medical device does not have to do that, theres a very, very low level of evidence thats required in order to get one of these approved. So thats why none of these questions that I raised have been necessarily answered. These products are safe, they dont cause any sort of damage necessarily but do they really work in healing wounds. And they are really considered because theres so many of them are out there and they are so pervasive that considered by many to be the gold standard in wound care but I have ask, whats that based on, wheres the science?
The Cochrane collaboration is the independent organization that does systematic reviews of medical literature on all sorts of medical topics. So basically youve find this reviews dealing with anything in medicine. Well just within the last few months in early 2009, they published review of the use of silver dressings in wound care. I think its important to go over their findings. Basically the Cochrane collaboration found only three randomized controlled trials on silver dressings. This contain 847 total patients and they were basically three study designs, one was silver-containing foams versus foam alone, one was silver containing alginate versus alginate alone and was silver containing foam versus the so-called best local practice.
This is a graphical representation of the Cochrane collaboration review of the silver compounds and basically what they do is they pull the literature from all over the world, from all over the worlds databases. And they found over 400 citations that mentioned silver dressings in wounds. Well, you can see by following the schematic when they window this down, this is how they came of with only three randomized controlled clinical trials. So the numbers of studies that are really supporting silver are very, very minimal.
So what did the review shell? Well the studies, the three randomized controlled studies that were available showed that the silver did not increase complete healing. So that semi answers one of the questions that I asked in the three basic questions. However there was a greater reduction in size of the wounds noted with silver and leakage occurred less frequently with silver dressings that were used, kind of gets back to that original uses of silver Id talked about making dressing changes less frequent and a little bit messy. But there was no difference at all in the use of systemic antibiotics in pain, in patients satisfaction or in length of stay.
So what did the Cochrane collaboration conclude after doing a systematic review of the world literature on silver-containing products? And this is a direct quote right from the review article itself. There is insufficient evidence to recommend the use of silver containing dressings or topical agents for treatment of infected or contaminated chronic wounds. Now please dont misunderstand me. Im not saying these silver dressings are bad. They may be very useful, I use them myself. The problem Ive got is just like with all of these other topical antiseptics and topical antimicrobials; there is just not enough good clinical evidence to back their use. They havent answered those three basic questions which I raised earlier on.
Well Ive reviewed the topical antibiotics that are available and the silver-containing products. Lets now look at some of these miscellaneous topical antimicrobials that may find use in wound care. First, weve got products that contain oak bark extract. Well oak bark extract releases metal ions that are then acidified in the presence of citric acid. And this has been shown to possibly potentiate some wound healing. Interestingly, there is some in vitro data that suggest that oak bark extract containing products are actually effective against the MRSA. In fact, in some data thats available from the ___ Corporation they found that 98.2% of that MRSA was reduced with 6 hour exposure to oak bark extract containing product. And this increased even marginally to 99.2% reduction in 24 hours. And again, this is in vitro data that may translate into in vivo data clinical data. We just dont really have that.
Another category of topical antimicrobial are the chlorine-based solutions and this include Dakin solution which is sodium hypochlorite, or essentially dilute Clorox bleach, superoxidized water and commercially available is the product known as Dermacyn. And hypochlorous acid. Again these are all 510K devices, they dont have drug approvals, so the literature behind them at this point is still a little bit sparse.
This graph schematically demonstrates a little bit about chlorine chemistry, and you can see that the chlorine molecule is present in the blue line at a very low acidic pH and as that pH increases, free chlorine actually diminishes, hypochlorous acid which is HOCL increases and actually peaks in a more neutral pH around 5-½ to 7 and then hydrochloride, sodium hydrochloride or bleach begins in a pH of around 5 or 6 and that increases at a very basic pH about 10. And you can see where along this continuum the various commercially available products do fall. Youve got vashe which is a hypochlorous acid solution that will be discussed in a second that peaks out in the neutral pH at about 5-½ to 6 which is hypochlorous acid, you can see that Dakin solution or sodium hypochlorite dilute bleach is the most basic of the compounds and you see that the Dermacyn or the superoxidized water is this blend of both hypochlorous acid and hypochlorite at a slightly lower more basic pH which does landed some more stability and shelf life but may cause some problems with patients tolerating it.
Superoxidized water or Dermacyn solution is been available for a while as a wound cleansing agent and its been shown in one small study that was presented by Adam Landsman at the International Diabetic Foot Congress in 2008 to be comparable to saline + levofloxacin for the clinical success of treating mildly infected diabetic foot ulcerations. Interestingly though, it was actually found to be less active microbiologically, so this gets back to what were talking about a little earlier, even in the presence of bacteria, sometimes wounds will heal, so here the wound heal despite this combination or the Dermacyn being less microbiologically active than the saline + levofloxacin, and there were relatively rare adverse events, only 1 out of 45 patients demonstrated that. One small quasi-experimental trial demonstrated that there may be decreased healing times with the use of Dermacyn superoxidized and possibly decreased antibiotic usage. However, one small study that was published in the Journal of Wound Care demonstrated an unexpected 40% local pain with application causing discontinuation. So that maybe related to the pH of the finished product, again small study though.
Another topical chlorine based product that is available is called vashe, and this is a hypochlorous acid solution. Hypochlorous acid solution is basically the same chemical found within neutrophils thats used to kill the bacteria once the bacteria are phagocytized. Now this unlike the other products that are available in bottles that you buy, this is actually generated on the site because it doesnt have the shelf life because of its chemistry, you actually have a generator that makes a batch of this fresh for every patient and then once the particular product is made for that patient, it is stable for a couple of days to a week or so. This is a pH neutral product, its not toxic tissues, in fact as I said before its the same chemical thats found within neutrophil so its the same chemical thats already found in the body. And because it has a neutral pH, you may have reduced incidence of localized stinging as opposed to some of the products that could be used that are in this chlorine based group. It is a broad spectrum antimicrobial and it may accelerate healing by generation of reactive oxygen species within the wound. Now all of these chlorine products do seem to have activity against bacteria, all of these may have activity healing the wound, and now what we need is to have those three questions answered for any of these products.
So in conclusion for part 2 of the lecture, I think its important to realize thats there really little high level evidence supporting the use of topical antimicrobials. And thats across the spectrum whether it be topical antibiotics, dressings or some of these newer chlorine-based solutions. Studies really need to be done to look all of these and determine their clinical efficacy. And I think there are three critical questions that need to be asked in these studies. 1) Does the product decolonize the wound? 2) Does the decolonization lead to faster wound healing? 3) And to me probably the most important, does decolonization of the wound decrease what could be an inevitable clinical infection? I want to thank you very much for your attention; I hope that you enjoy these lectures.
Production of this present lecture was made possible by a generous grant from PuriCore, developers of the exciting and new wound care technology; vashe wound therapy, the powerful nature of wound therapy.
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